The long-term goal of these studies is to understand the cellular and molecular control mechanisms of endochondral bone development. One objective of the work proposed is to understand how hypertrophic chondrocytes regulate the expression of various isoforms of vascular endothelial growth factor (VEGF) and cartilage angiogenesis at different developmental stages. A second objective is to gain insights into the role of hypertrophic chondrocytes in providing factors for local regulation of cellular differentiation. A third goal is to understand the role of the cherubism gene-the cytoplasmic adapter molecule SH3BP2-in regional control of bone formation and degradation. Finally, we aim at identifying novel regulators of chondrocyte hypertrophy and gene expression in hypertrophic chondrocytes. To reach those goals and objectives we will use a combination of mouse and human genetics and cell biological studies to study regulation of VEGF and blood vessel invasion into cartilage and the local control of differentiation of bone resorbing cells. The role of the signaling adapter molecule SH3BP2, mutated in families with cherubism, in osteoblast and osteoclast differentiation will e studied bone in human and mice. In cherubism, affected individuals suffer from severe disease. The studies will provide novel insights into bone formation and homeostasis and increase the understanding of both inherited and acquired bone disorders, including osteoporosis.